Effect of enterohepatic circulation on the pharmacokinetics of chloral hydrate and its metabolites in F344 rats

Chloral hydrate (CH) is a commonly found disinfection by-product in water p urification, a metabolite of trichloroethylene, arid a sedative/hypnotic dr ug. CH and two of its reported metabolites, trichloroacetic acid (TCA) and dichloroacetic acid (DCA), are hepatocarcinogenic in mice. Another metaboli te of CH, trichloroethanol (TCE), is also metabolized into TCA, and the ent erohepatic circulation (EHC) of TCE maintains a pool of metabolite for the eventual production of TCA. To gain insight on the effects of EHC on the ki netics of CH and on the formation of TCA and DCA, dual cannulated F344 rats were infused with 12, 48, or 192 mg/kg of CH and the blood, bile, urine, a nd feces were collected over a 48-h period. CH was cleared rapidly (>3000 m l/h/kg) and displayed biphasic elimination kinetics, with the first phase b eing elimination of the dose and the second phase exhibiting formation rate -limited kinetics relative to its TCE metabolite. The effects of EHC on met abolite kinetics were only significant at the highest dose, resulting in a 44% and 17% decease in the area under the curve (AUC) of TCA and TCE, respe ctively. The renal clearance of CH, free TCE (f-TCE), and TCA of 2, 2.7, an d 38 ml/h/kg, respectively, indicates an efficient reabsorption mechanism f or all of these small chlorinated compounds. DCA was detected at only trace levels (<2 mu M) as a metabolite of CH, TCA, or TCE.